Heterocyclic derivatives of guanidine

Abstract

5-Membered, 6-membered and 7-membered heterocyclic derivatives of guanidine having hypoglycemic activity.

I claim: 
     
       1. A heterocyclic derivative of guanidine selected from the group consisting of a compound having the formula: ##STR237## and the pharmaceutically acceptable acid addition salts thereof wherein: A is a member selected from the group consisting of O and S; n is the integer 0, 1, 2, 3;   m is the integer 0, 1, 2, 3, provided that n+m=1, 2, or 3;   R 1  is a member selected from the group consisting of methyl and ethyl;   R 2  is a member selected from the group consisting of loweralkyl, cyclopentyl, cyclohexyl, and benzyl; ##STR238##  taken together represents a member selected from the group consisting of: ##STR239##  wherein W is a member selected from the group consisting of O, S, N-loweralkyl and N-aryl; and R 3  is a member selected from the group consisting of: alkyl having from 4 to 10 carbons;   phenyl, methylenedioxypheny; phenyl substituted with from 1 to 3 substituents each selected from the group consisting of halo, loweralkyl and loweralkoxy; phenyl substituted with a member selected from the group consisting of hydroxy, benzyloxy, loweralkanoyloxy, nitro; trifluoromethyl and methylthio;   naphthyl;   cyclopentyl; cyclohexyl;   exo-2-norbornyl; endo-2-norbornyl; 1-adamantyl;   arylalkyl in which the aryl function is phenyl and the alkyl function has from 1 to 4 carbons; and   diphenylalkyl in which the alkyl function has from 1 to 2 carbons;     R 4  is a member selected from the group methyl, ethyl, n-propyl, i-propyl, n-butyl and isobutyl;   R 5  is H or loweralkyl having from 1 to 4 carbons; and   R 6  is H or loweralkyl having from 1 to 4 carbons.   
     
     
       2. A compound selected from the group consisting of N-(3-methyl-2-thiazolidinylidene)-N'-phenyl-1-pyrrolidinecarboximidamide and the pharmaceutically-acceptable acid addition salts thereof. 
     
     
       3. A compound selected from the group consisting of N-(3-methyl-2-thiazolidinylidene)-N'-phenyl-4-morpholinecarboximidamide and the pharmaceutically-acceptable acid addition salts thereof. 
     
     
       4. A compound selected from the group consisting of N-(4-methoxyphenyl)-N'-(3-methyl-2-thiazolidinylidene)-1-piperidinecarboximidamide and the pharmaceutically-acceptable acid addition salts thereof. 
     
     
       5. A compound selected from the group consisting of N-(3-methyl-2-oxazolidinylidene)-N'-phenyl-1-pyrrolidinecarboximidamide and the pharmaceutically-acceptable acid addition salts thereof. 
     
     
       6. A compound selected from the group consisting of N-(2,3,5,6-tetrahydro-4-methyl-1,4-oxazine-3-ylidene)-N'-phenyl-1-pyrrolidinecarboximidamide and the pharmaceutically acceptable acid addition salts thereof. 
     
     
       7. A compound selected from the group consisting of N-(4-hydroxyphenyl)-N'-(3-methyl-2-thiazolidinylidene)-1-piperidinecarboximidamide and the pharmaceutically-acceptable acid addition salts thereof. 
     
     
       8. A compound selected from the group consisting of N-{[(2,3,5,6-tetrahydro)-4-methyl]-1,4-thiazin-3-ylidene}-N'-(4-methoxyphenyl)-1-piperidinecarboximidamide and the pharmaceutically-acceptable acid addition salts thereof. 
     
     
       9. A compound selected from the group consisting of N-(4-methoxyphenyl)-N'-(4,5-dimethyl-3-thiomorpholinylidene)-1-pyrrolidinecarboximidamide and the pharmaceutically-acceptable acid addition salts thereof. 
     
     
       10. A compound selected from the group consisting of N'-(4-methylphenyl)-N-(3-methyl-2-thiazolidinylidene-4-morpholinecarboximidamide and the pharmaceutically-acceptable acid addition salts thereof. 
     
     
       11. A compound selected from the group consisting of N-(3-methyl-2-thiazolidinylidene)-N'-(3,4-methylenedioxyphenyl)-4-morpholinecarboximidamide and the pharmaceutically-acceptable acid addition salts thereof. 
     
     
       12. A compound of formula (II) or a pharmaceutically acceptable acid addition salt thereof: ##STR240## wherein X represents oxygen or sulfur; n represents zero, 1, 2 or 3;   m represents zero, 1, 2 or 3, provided that m+n=1, 2, or 3;   R 7  represents hydrogen or C 1-4  alkyl;   R 1  and R 2  are the same or different and represent hydrogen or C 1-4  alkyl, and at least one of R 7 , R 1  or R 2  is hydrogen;   R 3  represents methyl, ethyl, n-propyl, iso-propyl, n-butyl and isobutyl;   R 4  represents C 1-2  alkyl;   R 5  represents C 1-4  alkyl; C 3-6  cycloalkyl; or aralkyl in which the aryl function is a member selected from phenyl and naphthyl and the alkyl group has from 1 to 4 carbon atoms; or R 4  and R 5  together represent the remaining members of a 5- or 6-membered ring, the latter ring optionally containing an oxygen, sulfur or additional nitrogen atom at the 4-position relative to the first nitrogen atom, said additional nitrogen, when present, being the nitrogen of N-C 1-4  alkyl or N-aryl in which the aryl function is a member selected from phenyl and naphthyl; and   R 6  represents phenyl, optionally substituted with up to 3 groups selected from halogen, C 1-4  alkyl, C 1-4  alkoxy, or phenyl substituted with a member selected from hydroxy, benzyloxy, C 1-4  alkanoyloxy, nitro, trifluoromethyl, methylthio and isopropenyl; methylenedioxyphenyl; C 4-10  alkyl; naphthyl; C 5-8  cycloalkyl; exo-2-norbornyl, endo-2-norbornyl; 1-adamantyl; arylalkyl in which the aryl function is a member selected from phenyl and naphthyl and the alkyl group has from 1 to 4 carbon atoms; and diphenylalkyl in which the alkyl function has 1 to 2 carbons.   
     
     
       13. A compound as claimed in claim 12 wherein n is 1 and m is zero. 
     
     
       14. A compound as claimed in claim 12 wherein R 7  is hydrogen, and m+n=2. 
     
     
       15. A compound as claimed in claim 12 selected from the following or their pharmaceutically acceptable acid addition salts thereof: N-(3-methylthiazolidin-2-ylidene)-N'-phenyl-1-pyrrolidine carboxamidine;   N-(3-methylthiazolidin-2-ylidene)-N'-(4-methoxyphenyl)-1-piperidine carboxamidine;   N-(3-methylthiazolidin-2-ylidene)-N'-(3-chloro-4-methylphenyl)-1-(4-methylpiperazine) carboxamidine;   N-(3-methylthiazolidin-2-ylidene)-N'-phenyl-1-morpholine carboxamidine;   N-(3-methylthiazolidin-2-ylidene)-N'-(3-ethylphenyl)-1-pyrrolidine carboxamidine;   N-(3-methylthiazolidin-2-ylidene)-N'-(2-chlorophenyl)-1-pyrrolidine carboxamidine;   N,N-diethyl-N'-(3-ethylthiazolidin-2-ylidene)-N"-(4-bromophenyl)guanidine;   N-(3-methylthiazolidin-2-ylidene)-N'-(4-trifluoromethylphenyl)-1-thiomorpholine carboxamidine;   N'-(2-chlorophenyl)-N-(3-methylthiazolidin-2-ylidene)-1-morpholine carboxamidine;   N'-(4-bromophenyl)-N-(3-methylthiazolidin-2-ylidene)-1-(4-phenylpiperazine) carboxamidine;   N'-(4-bromo-3-chlorophenyl)-N-(3-methylthiazolidin-2-ylidene)-1-pyrrolidine carboxamidine;   N,N-diethyl-N'-(3-methylthiazolidin-2-ylidene)-N"-(2-chloro-5-trifluoromethylphenyl)guanidine;   N'-(2,4-difluorophenyl)-N-(3-methylthiazolidin-2-ylidene)-1-morpholine carboxamidine; and   N-(3-methyloxazolidin-2-ylidene)-N'-phenyl-1-pyrrolidine carboxamidine.   
     
     
       16. A compound of formula (II) or a pharmaceutically acceptable acid addition salt thereof: ##STR241## wherein X represents oxygen or sulfur; n represents zero or 1;   R 7  represents hydrogen or C 1-4  alkyl;   R 1  and R 2  are the same or different and represent hydrogen or C 1-4  alkyl, and at least one of R 7 , R 1  or R 2  is hydrogen;   R 3  represents methyl, ethyl, n-propyl, iso-propyl, n-butyl and isobutyl;   R 4  represents C 1-2  alkyl;   R 5  represents C 1-4  alkyl; C 3-6  cycloalkyl; or aralkyl in which the aryl function is a member selected from phenyl and naphthyl and the alkyl group has from 1 to 4 carbon atoms; or R 4  or R 5  together represent the remaining members of a 5- or 6-membered ring, the latter ring optionally containing an oxygen, sulfur or additional nitrogen atom at the 4-position relative to the first nitrogen atom, said additional nitrogen, when present, being the nitrogen of N-C 1-4  alkyl or N-aryl in which the aryl function is a member selected from phenyl and naphthyl; and   R 6  represents phenyl, optionally substituted with up to 3 groups selected from halogen, C 1-4  alkyl, C 1-4  alkoxy, or phenyl substituted with a member selected from hydroxy, benzyloxy, C 1-4  alkanoyloxy, nitro, trifluoromethyl, methylthio and isopropenyl; and methylenedioxyphenyl.   
     
     
       17. A compound as claimed in claim 16 wherein R 1  and R 2  represent hydrogen. 
     
     
       18. A compound as claimed in claim 16 wherein R 3  represents methyl, ethyl, n-propyl, iso-propyl, n-butyl or isobutyl. 
     
     
       19. A compound as claimed in claim 18 wherein R 3  represents methyl or ethyl. 
     
     
       20. A compound as claimed in claim 16 wherein R 4  and R 5  together represent the remaining members of a 5- or 6-membered ring, the latter ring optionally containing an oxygen, sulfur or additional nitrogen atom at the 4-position relative to the first nitrogen atom, said additional nitrogen, when present, being the nitrogen of N-C 1-4  alkyl or N-aryl in which the aryl function is a member selected from phenyl and naphthyl. 
     
     
       21. A compound as claimed in claim 20 wherein R 4  and R 5  complete a pyrrolidine, piperidine, morpholine, thiomorpholine, 4(C 1-4  alkyl)piperazine or 4(phenyl)piperazine. 
     
     
       22. A compound as claimed in claim 20 wherein the ring is unsubstituted, or substituted on said optional, additional nitrogen atom, when present, with C 1-4  alkyl or phenyl. 
     
     
       23. A compound as claimed in claim 16 wherein R 4  and R 5  together represent --(CH 2 ) 4  --, --(CH 2 ) 2  O(CH 2 ) 2  --, or --(CH 2 ) 2  NR x  (CH 2 ) 2  -- in which R x  is C 1-4  alkyl or aryl in which the aryl function is a member selected from phenyl and naphthyl. 
     
     
       24. A compound as claimed in claim 16 having formula (III) or a pharmaceutically acceptable acid addition salt thereof: ##STR242## wherein R 8  and R 9  represent hydrogen or C 1-4  alkyl; R 10  is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl and isobutyl;   R 11  and R 12  together represent the remaining members of a 5- or 6-membered ring, the latter ring optionally containing an oxygen or an additional nitrogen atom at the 4-position relative to the first nitrogen atom, said additional nitrogen atom, when present, being the nitrogen atom of N-C 1-4  alkyl of N-aryl in which the aryl function is a member selected from phenyl and naphthyl; and   R 14  represents hydrogen, C 1-4  alkyl, halogen, trifluoromethyl, methylthio, isopropenyl or benzyloxy.   
     
     
       25. A compound as claimed in claim 16 wherein n is zero. 
     
     
       26. A compound as claimed in claim 16 wherein R 7  is hydrogen and n is one. 
     
     
       27. A compound as claimed in claim 16 selected from the following or their pharmaceutically acceptable acid addition salts thereof: N-(3-methylthiazolidin-2-ylidene)-N'-phenyl-1-pyrrolidine carboxamidine;   N-(3-methylthiazolidin-2-ylidene)-N'-phenyl-1-morpholine carboxamidine;   N-(3-methylthiazolidin-2-ylidene)-N'-(2-chlorophenyl)-1-pyrrolidine carboxamidine; and   N-(3-methyloxazolidin-2-ylidene)-N'-phenyl-1-pyrrolidine carboxamidine.   
     
     
       28. A compound of the formula ##STR243## and the pharmaceutically acceptable acid addition salts thereof wherein: A is a member selected from the group consisting of O and S; n is the integer 0, 1, 2 or 3;   m is the integer 0, 1, 2 or 3, provided that when n is 0, m=3; when n is 1, m=1 or 2; when n is 2, m=0 or 1; and when n is 3, m=0;   R 1  is a member selected from the group consisting of methyl and ethyl;   R 2  is a member selected from the group consisting of loweralkyl, cyclopentyl, cyclohexyl and benzyl;   R 1  and R 2  taken together with the commonly attached nitrogen atom, represents a member selected from the group consisting of: ##STR244##  wherein W is a member selected from the group consisting of O, S, N-loweralkyl and N-aryl;   R 3  is a member selected from the group consisting of phenyl, methylenedioxyphenyl, phenyl substituted with from 1 to 3 substituents each selected from the group consisting of halo, loweralkyl, and loweralkoxy; and phenyl substituted with a member selected from the group consisting of hydroxy, benzyloxy, loweralkanoyloxy, nitro trifluoromethyl and methylthio;   R 4  is a member selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl and isobutyl;   R 5  is H or loweralkyl having from 1 to 4 carbons; and   R 6  is H or loweralkyl having from 1 to 4 carbons.   
     
     
       29. A pharmaceutical composition for the treatment of diabetes which comprises a compound, or a pharmaceutically acceptable acid addition salt thereof, as claimed in claim 16 together with a pharmaceutical carrier or excipient said compound or salt being present in an amount effective against diabetes. 
     
     
       30. An anti-diabetic composition according to claim 29 in orally or parenterally administrable form. 
     
     
       31. An antidiabetic composition in which the anti-diabetic agent is a compound of claim 27 and is present in an amount effective against diabetes. 
     
     
       32. A method of treating diabetes which comprises administering orally or parenterally to a diabetic host in need thereof an anti-diabetic amount of a composition of claim 29. 
     
     
       33. A method according to claim 32 wherein the composition is in unit dosage form.